Aging is a complex process affecting virtually all vital parameters of an organism, characterized by an overall decrease in many cellular functions that lead to increasing risk of disease and death. As the proportion of the aging population continues to grow worldwide, so does the incidence of developing age-related disorders, with the most devastating affecting the aging brain, such as dementia and Alzheimer's disease. Thus, there is a tremendous need to discover novel treatments to increase the health of the aging populace. For years, alterations in gene expression patterns have been shown to correlate with the human aging experience, but what drives such changes is not known. Emerging evidence suggests that epigenetic changes at the chromatin level are largely responsible; however, their precise role in the aging process has been untested due to the lack of experimental models. In order to directly test the cause and effect of epigenetic changes during aging, we have generated a novel mouse model, denoted the ICE mouse for inducible changes in the epigenome, which will allow me to elicit epigenetic changes by inducing non-mutagenic, site-specific nuclear DNA breaks at a few genomic sites using tamoxifen. Because the ICE system allows for both accurate temporal and spatial control of the epigenetic changes, I will be able to test whether modifications at the chromatin level are cause or effect of disorders that specifically affect the brain, such as cognitive decline and Alzheimer's disease. Results to date support the hypothesis that alterations to the epigenome can trigger aging acceleration in mammals. This project aims to develop a neuronal-specific ICE mouse in order to illuminate the underlying mechanisms that drive age-related cognitive impairment (Aim 1), use the ICE system to determine if epigenetic changes can drive the onset and progression of Alzheimer's disease (Aim 2), and study how chromatin modifications specifically disrupt the mitochondria during dementia and neurodegeneration (Aim 3). Taken together, this project will provide new valuable insights into the underlying mechanisms of the aging process, focusing on brain aging disorders, reveal potential biomarkers, and highlight therapeutic strategies to improve the human condition. Portions of all three Aims will start during the K99 training phase, under the mentorship of Dr. David Sinclair, an expert in epigenetics and aging, and Dr. Li-Huei Tsai, a leader in brain aging and Alzheimer's disease, with the work taking place at Harvard Medical School, an exceptional academic and research institution. Aspects of all three Aims will continue during the R00 independent phase. The funds will allow me to expand my research into new directions with regards to new techniques, knowledge, and concepts, working at the interface of neuroscience, aging, disease, and mitochondrial biology. Thus, I will be able to develop my own research niche that I will expand upon when starting my own research group.